Process for the preparation of 17alpha-dihydroequilenin and related compounds



United States Patent 3,507,889 PROCESS FOR THE PREPARATION OF 170:-

DIHYDROEQUILENIN AND RELATED COMPOUNDS David J. Marshall, Hampstead,Quebec, Canada, assignor to American Home Products Corporation, NewYork, N.Y., a corporation of Delaware No Drawing. Filed June 11, 1968,Ser. No. 735,978 Int. Cl. C07c 167/26 US. Cl. 260-3975 3 Claims ABSTRACTOF THE DISCLOSURE There is a disclosed herein a process for preparing17ozdihydroequilenin comprising reacting the benzyl or 2-tetrahydropyranyl ether or equilenin with an aryl sulfonylhydrazide toobtain the corresponding sulfonyl hydrazone, treating the latter withlithium aluminium hydride or with an alkyllithium compound to obtain thecorresponding 3- ether of estra-l,3,5(10),6,8,16 hexaene, reacting thelatter compound with an organic peracid to obtain the corresponding3-ether of 16a,l7a-epoxyestra-1,3,5(l0),6,8- pentaene, reducing saidlast-named compound with lithium aluminium hydride to the corresponding3-ether of 170:- dihydroequilenin said obtaining. 17a-dihydroequilenintherefrom by removal of the ether group. 17a-dihydroequilenin is anatural occurring estrogen, also useful as an intermediate in thepreparation of 17a-dihydroequilin, and a method for that latterconversion is also given.

The present invention relates to a process for preparing17a-dihydroequilenin, a naturally occurring estrogen which is alsouseful as an intermediate in the preparation of 17a-dihydroequilin, alsoa naturally occurring potent estrogen. The process for converting17a-dihydroequilenin to 17a-dihydroequilin is described in my co-pendingUS.

"patent application S.N. 653,009, filed July 13, 1967, now

(O KY 3,507,889 Patented Apr. 21, 1970 converted to its benzyl orZ-tetrahydropyranyl ether (II) (R=benzyl or Z-tetrahydropyranyl). Theether derivative of Formula II is allowed to react with an arylsulfonylhydrazide, for example, phenyl, p-tolyl, p-bromophenyl,p-chlorophenyl or 2-naphthylsulfonylhydrazide to yield the correspondingsulfonylhydrazide of Formula III in which R represents the phenyl-, thep-tolyl-, the p-bromophenyl, the p-chlorophenyl or the Z-naphthyl group.

Treatment of this last-named compound of Formula III with lithiumaluminum hydride or with an alkyllithium compound such as, for example,methyllithium or n-butyllithium, eliminates the sulfonylhydrazone groupand introduces a double bond in the 16,17-position to give thecorresponding 3-ether of estra-1,3,5(10),6,8,l6-hexane of Formula IV.Treatment of said last-named compound with an organic peracid such as,for example, peracetic, perbenzoic, m-chloroperbenzoic ormonoperphthalic acid gives the corresponding S-ether orl6a,17a-epoxyestra- 1,3,5 10),6,8-pentaene of Formula V. Reduction ofsaid last-named compound with lithium aluminum hydride than yields thecorresponding 3-ether of l7a-dihydroequilenin of Formula VI from which17a-dihydroequilenin (VII) is obtained by hydrogenolysis of the 3-benzyl ether group for example with palladium on carbon. AZ-tetrahydropyranyl group in postion 3 of compound VI is removed bytreatment with dilute mineral acid in solution in a lower alkanol alsoto give 17u-dihydroequilenin.

If it is desired to prepare 17a-dihydroequilin, I prefer to usel7a-dihydroequilenin 3-benzyl ether (VI, R=benzyl) as the startingmaterial and converting said compound to its 17-(2-tetrahydropyranyl)ether of Formula VIII by treating it with dihydropyran in the presenceof an acid catalyst for example, p-toluenesulfonic acid. Hydrogenolysisof said last-named compound for example, with palladium on carbon yields17adihydroequilenin 17-(2-tetrahydropyranyl) ether of Formula IX.

Reduction of said last-named compound with an alkali metal such aslithium, sodium, or potassium in liquid ammonia in the same manner asdescribed in my co-pending US. patent application cited above, followedby acid hydrolysis of the tetrahydropyranyl ether group yields17adihydroequilin of Formula X.

The following examples and formulae, in which R represents the benzyl orthe Z-tetrahydropyranyl group and R represents an aryl group as definedabove, will illustrate this invention.

2 ,2 li i 13" R O R O 4 (VI) (V) 2 l lfi Vii (VII) (VIII) EXAMPLE 1Equilenin benzyl ether p-toluenesulfonylhydrazone To a solution of 29.1g. of equilenin benzyl ether (Heer, Billeter and Miescher, Helv. Chim.Acta. 28, 991 (1945)) in 290 ml. of Warm benzene is added 29 g. ofp-toluenesulfonylhydrazide and 204 ml. of ethanol. The solution isheated under reflux for 24 hours, cooled, and filtered, yielding thetosylhydrazone as a colourless solid, M.P. 226-227 C. (dec.).

-By substituting benzenesulfonylhydrazide,p-bromobenzenesulfonylhydrazide, p-chlorobenzenesulfonylhydrazide orZ-naphthylsulfonylhydrazide for p-toluenesulfonylhydrazide in the aboveexperiment, the corresponding sulfonylhydrazones of equilenin benzylether can be obtained.

EXAMPLE 2 Equilenin 2-tetrahydropyranyl ether p-toluenesulfonylhydrazoneA mixture of 2.0 g. of equilenin, 1 ml. of dihydropyran and 40 mg. ofp-toluenesulfonic acid in 20 ml. of benzene is stirred at roomtemperature for 2 hours. The acid is neutralized with pyridine and thesolution is washed with water, dried and evaporated. To the residue isadded 2.8 g. of p-toluenesulfonylhydrazide and 40 ml. of methanol andthe solution is heated under reflux for 4 hours. Concentration anddilution with water gives the toluenesulfonylhydrazone as a pinkishsolid, M.P. 238-240 (dec.).

- EXAMPLE 3 3-benzyloxyestra-1,3,5 10) ,6,8,16-hexaene Equilenin benzylether p-tosylhydrazone (36.0 g.) is added to a stirred solution ofmethyllithium (made from 46.0 g. of methyl iodide and 4.1 g. of lithiumwire in 500 ml. of ether) under nitrogen. The hydrazone slowly dissolveswith gas evolution and the mixture becomes red- A. PO

2H li HO )W EXAMPLE 4 3-(Z-tetrahydropyranyloxy)estra-1,3,5(10),6,8,16-hexaene To a suspension of 2.8 g. of lithium aluminium hydride in 50 ml.of dioxane is added 1.8 g. of equilenin 2-tetrahydropyranyl etherp-toluenesulfonylhydrazone in 30 ml. of tetrahydrofuran and the mixtureis stirred and heated under reflux overnight. Ethyl acetate is addedfollowed by saturated aqueous potassium sodium tartrate solution toprecipitate the inorganic salts. Filtration, evaporation, andchromatography on silica gel gives the hexaene, characterized by a bandat 720 cm.- in its infrared spectrum.

EXAMPLE 5 3-benzyloxy-16u,17a-epoxyestra-1,3,5(10),6,8-pentaene To astirred solution of 11.8 g. of 3-benzyloxyestra- 1,3,5 (),6,8,16-hexaenein 60 m1. of benzene and 60ml. of ethyl acetate containing 12.0 g. ofanhydrous sodium acetate is added dropwise ml. of peracetic acid.

After stirring at room temperature overnight and then at C. for 2 hours,the mixture is diluted with benzene and washd with water, sodiumbicarbonate solution and water again. The crude product obtained ondrying and removal of solvent is crystallized from methylenechloride-methanol yielding the epoxide, M.P. 176177.5.

Similar treatment of 3-(Z-tetrahydropyranyloxy)-estra- 1,3,5(10),6,8,l6-hexaene with peracetic, m-chloroperbenzoic, perbenzoic, ormonoperphthalic acid leads to 3- (2 tetrahydropyranyloxy) 1611,17uepoxyestra 1,3,5(10),6,8-pentaene.

EXAMPLE 6 3-benzyloxyestra-l,3,5( 10) ,6,8-pentaen-l7a-ol To a stirredsuspension of 3.0 g. of lithium aluminium hydride in 75 ml. of ether isadded dropwise a solution of 9.8 g. of3-benzyloxy-16a,17a-epoxyestra-1,3,5 (10)6,8- pentaene in 150 ml. oftetrahydrofuran. After heating under refiux for 2.5 hours, excesshydride is decomposed by adding ethyl acetate to the ice-cooled mixture,followed by saturated aqueous sodium potassium tartrate solution toprecipitate inorganic salts. The mixture is filtered and the solidobtained by evaporation of the filtrate is crystallized from methylenechloride-methanol to yield 3-benzylxyestra-1,3,5(lO),6,8-pentaen-17a-ol,M.P. 125127 C.

Similarly, reduction of 3-(Z-tetrahydropyranyloxy)- 16a,l7a-epoxyestra-1,3,5( 10) ,6,8-pentaene with lithium aluminium hydrideyields 3-(Z-tetrahydropyranyloxy)- estra-1,3,5(10),6,8-pentaen-17a-ol.

EXAMPLE 7 17a-dihydroequilenin (a) A solution of 500 mg. of3-benzyloxyestra- 1,3,5(l0),6,8-pentaen-17a-ol in 10 ml."of ethylacetate is hydrogenated at atmospheric pressure in the presence of 250mg. of 5% palladium on charcoal. When hydrogen absorption is complete,the catalyst is filtered, the filtrate is concentrated to dryness andthe residue is crystallized from acetone-hexane and then fromacetone-benzene to yield l7u-dihydroequilenin, M.P. 214216 C. Thiscompound is identical with 17a-dihydroequilenin obtained from naturalsources.

(b) To 500 mg. of 3-(Z-tetrahydropyranyloxy)estra-1,3,5(),6,8-pentaen-17a-ol in 10 ml. of methanol is added 1 ml. of 10%hydrochloric acid. After one hour at room temperature, dilution withwater and crystallization of the precipitated product yields17a-dihydroequilenin.

EXAMPLE 8 17 u- (Z-tetrahydropyranyloxy)estra-2,3,5 (10),6,8-pentaen-3-ol A mixture of 10.0 g. of-B-benzyloxyestra-1,3,5(10),6,8-pentaen-17a-ol, 160 mg. of p-toluenesulfonic acid and 7.5 ml. ofdihydropyran in 180 ml. of benzene is stirred at room temperature for 2hours. After neutralization with 0.3 ml. of pyridine, the solution iswashed with water, dried, and evaporated. The resulting oil is dissolvedin 150 ml. of ethyl acetate and hydrogenated at atmospheric pressure inthe presence of 6 gQof 5% palladium on carbon. When uptake of hydrogenceases after 2 hours, the catalyst is removed by filtration. Evaporationof solvent then gives 17a-(Z-tetrahydropyranyloxy)estra-1,3,5(10),6,8pentaen-3-ol as a pale yellow foam.

EXAMPLE 9 17a-dihydroequilin Sodium hydride (1.2 g. of 50% dispersion inmineral oil) is washed four times with petroleum ether by decantation.

The adhering solvent is blown off under a stream of nitrogen, 10 ml. oftetrahydrofuran is added, and a solution of 5.2 g. of17a-(Z-tetrahydropyranyloxy)-estra- 1,3,5(10),6,8-pentaen-3-ol in 50 ml.of tetrahydrofuran is added dropwise with stirring under nitrogen. Thesolution is stirred for 45 minutes and transferred to a dropping funnelattached to a flask containing a solution of 8.0 g. of potassium in ml.of liquid ammonia cooled to 70 C. in a Dry Ice-acetone bath. The stirredsolution is added dropwise over a period of 20 minutes and stirring iscontinued at 70 C. for one hour. Ammonium chloride is then added insmall portions until the colour is discharged and the ammonia is allowedto evaporate under a stream of nitrogen. Ether and water are added, andthe ether extract is washed with water, dried, and evaporated to give ayellow foam. This material is dissolved in 50 ml. of methanol and thesolution is treated with 5 ml. of 10% hydrochloric acid. After one hourat room temperature, the solution is diluted with water and extractedwith ether. The material obtained from the ether extract ischromatographed on silica gel and crystallized from aqueous methanol toyield 17a-dihydroequilin identical with material obtained from naturalsources.

In the same manner. when using equivalent amounts of lithium or sodiuminstead of potassium, 17a-dihydroequilin is also obtained.

I claim:

1. The process of preparing 17a-dihydroequilenin which comprisescohverting equilenin to an ether derivative thereof of formula wherein Rrepresents benzyl or the Z-tetrahydropyranyl group; treating said etherderivative with an aryl sulfonylhydrazide, thereby obtaining thecorresponding sulfonyl hydrazide derivative of formula lHNHSOzR IS lwherein R is as above defined, R represents phenyl, p-tolyl,p-bromophenyl, p-chlorophenyl or the Z-naphthyl group; treating saidsulfonylhydrazide derivative with a reagent selected from lithumaluminum hydride, methyllithium or n-butyllithium, thereby securing acompound wherein R is as above defined; treating said last-namedcompound with an organic peracid, thereby securing the corresponding3-ether derivative of formula .0 wily R being as above defined, treatingsaid 3-ether derivative with lithium aluminum hydride, thereby obtaininga compound of formula 2H lf] il J R being as above defined; andsubjecting said compound to hydrogenolysis by treating with hydrogen inthe presence of palladium catalyst, thereby securingl7a-dihydroequilenin.

2. The process of preparing 17cc dihydroequilenin which comprisesconverting equilenin to an ether derivative thereof of formula il Jwherein R represents benzyl or the Z-tetrahydropyranyl group; treatingsaid ether derivative with an aryl sulfonylhydrazide thereby obtainingthe corresponding sulfonyl hydrazide derivative of formula NNHS 02Rwherein R is as above defined, R represents phenyl, ptolyl, pbromophenyl, p-chlorophenyl or the Z-naphthyl group; treating saidsulfonylhydrazide derivative with a reagent selected from lithiumaluminum hydride, methyllithium or n-butyllithium, thereby securing acompound of the formula AK R wherein R is as above defined; treatingsaid last-named compound with an organic peracid, thereby securing thecorresponding 3-ether derivative of formula p3 nd With lithium aluminumhydride, thereby obtaining a compound of formula Q5 ild R being as abovedefined; and subjecting said compound to the action of a mineral acid,thereby securing 17ccdihydroequilenin.

3. The process of preparing l7u-dihydroequilin which comprises treatinga compound of the formula wherein R is benzyl with dihydropyran in thepresence of an acid catalyst, thereby securing a compound of formulasubjecting said compound to the action of hydrogen in the presence ofpalladium as catalyst, thereby securing 17adihydroequilenin l7 (2tetrahydropyranyl) ether of formula dd H003 'ELBERT L. ROBERTS, PrimaryExaminer US. Cl. X.R.

R being as above defined, treating said 3-ether derivative 260-43955

